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Journal of Virology, January 2000, p. 1057-1060, Vol. 74, No. 2
0022-538X/00/$04.00+0
Copyright © 2000, American Society for Microbiology. All rights reserved.
The Late Lytic LMP-1 Protein of Epstein-Barr Virus
Can Negatively Regulate LMP-1 Signaling
Kimberly D.
Erickson and
Jennifer M.
Martin*
Department of Molecular, Cellular, and
Developmental Biology, University of Colorado, Boulder, Colorado 80309
Received 16 August 1999/Accepted 8 October 1999
 |
ABSTRACT |
The BNLF-1 open reading frame of Epstein-Barr virus (EBV) encodes
two related proteins, latent membrane protein-1 (LMP-1) and lytic LMP-1
(lyLMP-1). LMP-1 is a latent protein required for immortalization of
human B cells by EBV, whereas lyLMP-1 is expressed during the lytic
cycle and is found in the EBV virion. We show here that, in contrast to
LMP-1, lyLMP-1 is stable, with a half-life of >20 h in tetradecanoyl
phorbol acetate- and butyrate-treated B95-8 cells. Although lyLMP-1
itself has negligible effects on NF-
B activity, it inhibits NF-B
activation by LMP-1 in a dose-dependent manner. The lyLMP-1 protein
does not oligomerize with LMP-1, and the negative effect of lyLMP-1 on
NF-B activation by LMP-1 does not result from lyLMP-1-mediated
disruption of LMP-1 oligomers. Modulation of LMP-1-activated signaling
pathways is the first identified biological activity associated with
lyLMP-1, and this activity may contribute to the progression of EBV's
lytic cycle.
| |
TEXT |
Epstein-Barr virus (EBV), a
ubiquitous human herpesvirus causally associated with several human
tumors (23), infects resting B cells and establishes a
latent infection resulting in unlimited proliferation. Latent membrane
protein-1 (LMP-1) is an essential viral membrane protein required for
immortalization by EBV and acts by regulating key cell signaling
pathways. Although EBV-infected B cells rarely enter the lytic cycle
and release virus (24, 30, 33), certain EBV-positive B-cell
lines can be induced to release infectious progeny through treatment
with agents such as tetradecanoyl phorbol acetate (TPA) and sodium
butyrate (10, 34, 35). Lytic cycle entry results in
temporally regulated expression of the majority of the viral genome
(~100 open reading frames [ORFs]) (2, 32).
One late lytic cycle promoter, EDL1A, lies within the LMP-1 gene and
drives the expression of a transcript encoding a predicted ORF
corresponding to an amino-terminally truncated form of LMP-1 (11). A protein in infected cells of molecular weight
predicted by this ORF has been termed lytic LMP-1 (lyLMP-1) because of
its expression during EBV's lytic cycle (1, 3, 7, 11, 29). The lyLMP-1 ORF begins at methionine 129 of the LMP-1 sequence and
continues through the fifth and sixth transmembrane domains and entire
carboxy terminus. lyLMP-1 shares none of LMP-1's known biological or
biochemical properties (19, 31), and little is known about
lyLMP-1's function in the infected cell. We reported previously that
lyLMP-1 is a component of the EBV virion and proposed a function in the
initial stages of infection and/or during the lytic cycle
(7). Its sequence identity with LMP-1 suggests that lyLMP-1
may interact with LMP-1 itself or with effectors of LMP-1 signaling. We
have begun to characterize the biochemical and biological properties of
lyLMP-1, with the goal of understanding its role in the virus life
cycle, and have tested the hypothesis that lyLMP-1 affects the ability
of full-length LMP-1 to activate cell signaling pathways.
De novo synthesis of lyLMP-1 in TPA- and butyrate-induced B95-8
cells.
Western blot analysis of permissive EBV-positive B-cell
lines induced to enter the lytic cycle often reveals a ladder of
LMP-1-immunoreactive proteins migrating with lower apparent molecular
weights than does LMP-1. Detection of this LMP-1 ladder of bands
depends upon the amount of LMP-1 expressed in the cell (reference
7 and unpublished observations). Whether these
LMP-1-related proteins are derived from proteolysis of LMP-1 (before or
after cell lysis) or from de novo translation initiating at internal
methionines in the LMP-1 ORF has been difficult to ascertain
(18). The 45-kDa LMP-1-immunoreactive protein, detected in
induced cells, migrates with a molecular mass consistent with that
reported for the migration of lyLMP-1 (1, 7) as determined
by sodium dodecyl sulfate-polyacrylamide gel electrophoresis
(SDS-PAGE).
To confirm that the 45-kDa lyLMP-1 protein arises from de novo
translation of the EDL1A transcript, we asked if a precursor-product relationship existed between LMP-1 and the 45-kDa protein. B95-8 cells
were cultured in 20 ng of TPA per ml and 3.5 mM sodium butyrate for
48 h and starved in methionine-free medium for 1 h, and then 1 mCi of Tran [35S]methionine (ICN) per ml was added for
an additional 20 min. Following the pulse, cells were grown in RPMI
1640-10% calf serum for up to 20 h. Cell pellets were
solubilized in 5× radioimmunoprecipitation assay [RIPA] buffer (100 mM Tris [pH 8.0], 150 mM NaCl, 0.1% SDS, 1% NP-40, 0.5%
deoxycholate) and sonicated, and LMP-1 proteins were immunoprecipitated
as described previously (21). Boiled samples were precleared
with protein G-agarose beads (Boehringer Mannheim), incubated with
polyclonal LMP-1 antiserum, and precipitated with protein G-agarose
beads. The LMP-1 antiserum was raised in rabbits against an LMP-1
carboxy terminus-glutathione S-transferase fusion protein.
Immunoprecipitates were resolved by SDS-PAGE and analyzed by
autoradiography (Fig. 1). If the 45-kDa
lyLMP-1 protein arises de novo from its own transcript, then it should
be detectable by autoradiography in cells labeled with
[35S]methionine for short periods without subsequent
chase. [35S]methionine-labeled 45-kDa lyLMP-1 was readily
detectable after the 30-min pulse and persisted, with a calculated
half-life of at least 20 h (Fig. 1). In contrast to lyLMP-1,
35S-labeled LMP-1 decreased over time and was undetectable
20 h following the pulse. Consistent with its reported rapid
turnover in other cells (1, 20, 21), the half-life of LMP-1
in TPA- and butyrate-treated B95-8 cells was between 3 and 6 h. It
is unlikely that radiolabeled lyLMP-1 results from LMP-1 degradation since a band comigrating with lyLMP-1 was not seen in
35S-labeled uninduced B95-8 cells, which express primarily
LMP-1 (not shown). Also, unlike the relationship between the loss of LMP-1 and the appearance of the ~40-kDa LMP-1 immunoreactive protein, there was no precursor-product relationship between LMP-1 and the
45-kDa lyLMP-1 protein (Fig. 1). These results provide experimental evidence for lyLMP-1's de novo translation from the EDL1A transcript in induced B95-8 cells. The difference in half-lives of the two LMP-1
proteins suggests distinct turnover mechanisms and is consistent with
previous results demonstrating a correlation between LMP-1's biological activity and rapid turnover (21). The long
half-life of lyLMP-1 is consistent with our observation that, once
carried into the infected cell with the virion, the protein remains
detectable for ~48 h, in the absence of de novo protein synthesis
(7). The persistence of lyLMP-1 protein in the cell early
after infection may be important for regulation of cellular signaling
pathways involved in establishment of immortalization.
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FIG. 1.
The half-life of the lyLMP-1 protein in B95-8 cells is
>20 h. Forty-eight hours after induction with TPA and butyrate, B95-8
cells were starved in methionine-free medium for 1 h, pulsed with
[35S]methionine for 20 min, and chased in RPMI 1640 plus
10% bovine calf serum (R10C) medium for the times indicated. LMP-1
proteins were immunoprecipitated from cell lysates with
affinity-purified anti-LMP-1 antiserum raised against LMP-1's carboxy
terminus. Immunoprecipitates were resolved by SDS-PAGE and visualized
by autoradiography. The hours of chase are the times prior to harvest
following a 30-min pulse with [35S]methionine; the upper
and lower arrows indicate the migrations of the 62-kDa full-length and
45-kDa lyLMP-1 proteins, respectively. Molecular mass markers are not
shown.
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Inhibition of LMP-1-stimulated NF-B activity by lyLMP-1.
The high levels of lyLMP-1 expressed during lytic cycle progression in
EBV-infected cells may affect the function of LMP-1 and thereby
contribute to the disruption of latency. Expression of LMP-1 in certain
cell lines results in upregulation of NF-B activity (20- to 50-fold)
(9, 12, 26). Tumor necrosis factor receptor-associated
factor (TRAF) binding to LMP-1's carboxy terminus is required for
NF-B activation (4, 14), and LMP-1 oligomerization is
proposed to be required for both TRAF binding and NF-B activation (8, 27). To determine whether expression of lyLMP-1 could affect LMP-1 activity, we coexpressed the two proteins in the human
embryonic kidney cell line 293 and assayed for NF-B activity (Fig.
2). 293 cells were
electroporated (Bio-Rad Gene Pulser) with a luciferase reporter driven
by the minimal fos promoter containing three upstream B
binding sites (p1242 [26]), pRSV-lacZ, and a constant
amount of pCMV-LMP-1, together with increasing amounts of pCMV-lyLMP-1.
pCMV-lyLMP-1 and pCMV-LMP-1 are pCDNA3-based expression vectors
encoding the lyLMP-1 and LMP-1 ORFs, respectively, under the control of
the cytomegalovirus promoter. Consistent with previous results, lyLMP-1
was deficient, relative to LMP-1, in its ability to activate NF-B
(Fig. 2A and C) (12, 26). Coexpression of lyLMP-1 and LMP-1
resulted in the inhibition of LMP-1-stimulated NF-B activity.
Maximal inhibition (~90%) of LMP-1-stimulated NF-B activity by
lyLMP-1 occurred when there was an ~18-fold excess of input
pCMV-lyLMP-1 relative to the input pCMV-LMP-1 (Fig. 2A and C). This
ratio of input DNA resulted in approximately equivalent expression
levels of the two LMP-1 proteins (Fig. 2B). LMP-1-stimulated NF-B
activity was inhibited dose dependently by coexpression of lyLMP-1
(Fig. 2C). These results demonstrate that lyLMP-1 can negatively
regulate LMP-1 signaling in 293 cells. Consistent with lyLMP-1's
potential to negatively regulate LMP-1 signaling in virus-infected
cells is the finding that the ratio of lyLMP-1 to LMP-1 required to
block LMP-1 signaling in 293 cells (Fig. 2B) is roughly equivalent to
the ratio of LMP-1 proteins in induced B95-8 cells (1, 7).
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FIG. 2.
Activation of NF-B by LMP-1 is inhibited by
coexpression of lyLMP-1. 293 cells were electroporated with 1 µg of
p1242 (luciferase reporter driven by the minimal fos
promoter with three upstream B sites), 1 µg of pRSV-lacZ, and 1.35 µg of pCMV-LMP-1, with and without increasing amounts of
pCMV-lyLMP-1. Forty-eight hours following transfection, cells were
harvested and samples were assayed for LMP-1 expression and NF-B
activity. Luciferase values were averaged for each sample and
normalized to averaged  -galactosidase values to yield relative light
units. The relative light units were averaged for each set of duplicate
transfections. (A) LMP-1 activation of NF-B activity in the presence
of lyLMP-1. Data are expressed as percentages of LMP-1-stimulated
NF-B activity; the percent NF-B activity attributed to lyLMP-1
alone (~20%) was considered background and subtracted from the
percent NF-B activity when both proteins were coexpressed. Hatched
bar, LMP-1 alone; open bar, 1.35 µg of pCMV-LMP-1 plus 4.05 µg of
pCMV-lyLMP-1; filled bar, 1.35 µg of pCMV-LMP-1 plus 24.3 µg of
pCMV-lyLMP-1. The ratios of the expression vectors (pLMP-1/pLyLMP-1)
are indicated below the graph. Each error bar represents the standard
error of mean of results from three experiments. The average fold
induction for lyLMP-1 alone was 5, and that for LMP-1 alone was 25. (B)
Western analysis of LMP-1 expression. Extracts of 2.5 × 103 cells from panel A were analyzed by Western blotting
with anti-LMP-1 antiserum. +, 1.35 µg of pCMV-LMP-1;  , absence of
the indicated LMP-1 expression vector; triangle, low (4.05 µg) and
high (24.3 µg) amounts of introduced pCMV-lyLMP-1; B95-8, extract of
5 × 104 B95-8 cells included as a marker for
migration of LMP-1 proteins; upper and lower arrows, migrations of
full-length and lyLMP-1 proteins, respectively. Sixty-eight- and 45-kDa
markers are indicated to the left of the blot. (C) Dose-dependent
inhibition of LMP-1-stimulated NF-B activity by lyLMP-1 expression.
Data are expressed as percentages of LMP-1-stimulated NF-B activity;
activity from lyLMP-1 alone was not subtracted from LMP-1 values. Open
circles, NF-B activity in cells expressing lyLMP-1; filled squares,
NF-B activity in cells transfected with 1.35 µg of pCMV-LMP-1 and
increasing amounts of pCMV-lyLMP-1.
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LyLMP-1 does not disrupt LMP-1 oligomerization.
LMP-1 is
believed to activate signaling pathways as a constitutive TRAF-binding
oligomer (4, 5, 13). Overexpression of lyLMP-1 (relative to
the level of LMP-1) may interfere with LMP-1 signaling by disrupting
LMP-1 oligomerization. High levels of lyLMP-1 may inhibit LMP-1
oligomerization by associating with LMP-1 and preventing formation of
full-length LMP-1 oligomers. To explore the mechanism by which lyLMP-1
inhibits LMP-1 signaling, we determined if lyLMP-1 either oligomerizes
with LMP-1 or alters LMP-1's ability to homo-oligomerize. To assess if
lyLMP-1 associates with LMP-1, pCMV-lyLMP-1 and
pCMV-LMP-1myc were cotransfected into 293 cells and 48 h later cell extracts prepared as described by Gires et al.
(8) were assayed for oligomerization by
coimmunoprecipitation with the anti-myc monoclonal antibody
9E10 (Santa Cruz Biochemicals) (Fig.
3). pCMV-LMP-1myc was
constructed from pCMV-LMP-1 by insertion of the myc epitope
tag (EQKLISEEDL) at LMP-1's carboxy terminus. pCMV-C
55 is an
expression vector encoding a mutant LMP-1 lacking the last
carboxy-terminal 55 amino acids and has been described previously
(22). The NP-40 soluble fraction was precleared with protein
G-agarose beads, and LMP-1 myc was immunoprecipitated from
the precleared supernatant with anti-myc antibody (9E10; Santa Cruz). Complexes were recovered by incubation with protein G-agarose beads, washed with 1× RIPA buffer, resuspended in 4× SDS
sample buffer, and analyzed by SDS-PAGE and Western blotting. lyLMP-1
was not detectable in LMP-1 myc immunoprecipitates, despite the large (
5-fold) excess of lyLMP-1 protein relative to the level of
LMP-1 myc protein (Fig. 3, lane 5). The inability of lyLMP-1
to coimmunoprecipitate with LMP-1 myc was not due to
immunoprecipitation conditions or to the presence of the myc
epitope tag at LMP-1's carboxy terminus since C55, a mutant LMP-1
lacking the last carboxy-terminal 55 amino acids, interacted
efficiently with LMP-1 myc (Fig. 3, lane 10). These results
are consistent with the work of Gires et al., demonstrating a role for
the amino terminus and transmembrane domains of LMP-1 in
oligomerization (8). Importantly, C55 was detected in
LMP-1 myc immunoprecipitates from cells coexpressing LMP-1
myc and lyLMP-1, indicating that lyLMP-1 did not interfere with LMP-1's ability to oligomerize (Fig. 3, lane 12). These results demonstrate that lyLMP-1 does not associate with LMP-1 and that it does
not prevent LMP-1 from forming homo-oligomers. It is unlikely, therefore, that lyLMP-1 inhibits LMP-1 signaling via disruption of
LMP-1 oligomerization.
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FIG. 3.
lyLMP-1 does not interfere with LMP-1 oligomerization.
293 cells were electroporated (conditions were as described in the Fig.
1 legend) with 1.5 µg of pCMV-LMP-1myc, with or without
either 25 µg of pCMV-lyLMP-1 or 5 µg of pCMV-C55. Cells were
transfected with equivalent amounts of the cytomegalovirus promoter
(pcDNA3) and equivalent amounts of total DNA. Forty-eight hours
following transfection, 5 × 106 cells were harvested
for immunoprecipitation (IP) and the remaining cells were used for the
whole-cell lysate sample (W). Lanes: W, 5 × 104 cell
equivalents of whole-cell lysate; IP, 1.25 × 106 cell
equivalents of immunoprecipitated samples. The presence (+) or absence
() of the transfected expression vector is indicated above the blot.
The upper and lower arrows indicate the migrations of the full-length
LMP-1 and lyLMP-1 or C55 proteins, respectively; 87-, 64-, and
52-kDa molecular mass markers are indicated by bars to right of the
blot.
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Immortalization of human B cells by EBV is complex and results from the
expression of several viral gene products, one of
which is LMP-1. Since
expression of LMP-1 proteins is restricted
to full-length LMP-1 in
latently infected lymphoblastoid cell
lines, we think it unlikely that
lyLMP-1 plays a role in the maintenance
of immortalization. This
conclusion is supported by the observation
that lymphoblastoid cell
lines infected with recombinant EBV and
expressing LMP-1 proliferate
despite the presence in these cells
of LMP-1 immunoreactive,
smaller-molecular-weight proteins (
15).
LMP-1 can activate
divergent signaling pathways (
6,
16,
17,
25). Not all
LMP-1-activated pathways are likely to be required
for immortalization
(
16,
28), and overexpression of lyLMP-1
may not regulate all
LMP-1-activated
signaling.
The high level of expression of lyLMP-1 in virus-producing cells
suggests a function during the lytic cycle, and the presence
of lyLMP-1
protein in the EBV virion suggests a role shortly after
infection.
lyLMP-1 can negatively affect LMP-1 function in 293
cells without
disrupting LMP-1 oligomerization. These observations
are consistent
with a model in which the lyLMP-1 protein may downregulate
NF-
B
activation in the late stages of lytic infection by negatively
affecting the function of LMP-1. In addition, lyLMP-1 has the
potential
to regulate signaling in infected cells in an LMP-1-independent
manner,
i.e., upon virus entry prior to LMP-1 expression (
7).
Studies are in progress to determine the mechanism by which lyLMP-1
affects LMP-1-regulated pathways and to identify the role of lyLMP-1
in
EBV's life
cycle.
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ACKNOWLEDGMENTS |
We thank Brad Olwin, Tin Tin Su, and members of the Martin
laboratory for critical reading of the manuscript.
This work was supported by NIH CA-64610-06 and AI-01537-02 grants to
J.M.M.
| |
FOOTNOTES |
*
Corresponding author. Mailing address: Department of
Molecular, Cellular, and Developmental Biology, University of Colorado, Box 347, Boulder, CO 80309. Phone: (303) 492-6346. Fax: (303) 492-1587. E-mail: jm{at}stripe.colorado.edu.
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Journal of Virology, January 2000, p. 1057-1060, Vol. 74, No. 2
0022-538X/00/$04.00+0
Copyright © 2000, American Society for Microbiology. All rights reserved.
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